SPRINT-MS: A high-throughput platform for identifying protein-protein interactions using pooled IP-MS and sparse signal recovery

We present SPRINT-MS (SParse Reconstruction of INTeractions by Mass Spectrometry), an integrated experimental and computational platform to accelerate the discovery of protein-protein interactions (PPIs). PPIs, which govern critical cellular and physiological processes such as development and disease, form extensive networks that vary across time, conditions, and cell types, creating a complex, high-dimensionality problem. Thus, there is a pressing need for universally applicable tools capable of mapping and quantifying PPI networks and their context-dependent dynamics with high efficiency. SPRINT-MS combines an innovative antibody (or lysate) pooling scheme, immunopurification-mass spectrometry (IP-MS), and a novel sparse signal reconstruction algorithm to enable pooled PPI capture experiments. This approach increases throughput by an order of magnitude, while reducing sample input requirements. We demonstrate that SPRINT-MS, applied to 30 bait proteins of interest via either antibody or lysate pooling, is comparable to standard individual IP-MS experiments in the identification of PPIs and recapitulation of known interactions.